pointer to:Daniel MacArthur and Neil Walker’s (@ Genetic Future bog) in-depth coverage of various critiques on the recent back-to-back-to-back Nature magazine trifecta (covered here) on GWAS results for schizophrenia. Rough going for the global corsortia and a major f**king bummer for folks like myself who have been hoping that these vast studies would provide a solid basis for genome-based cognitive intervention strategies in the future. Some of the discussion in the comments section points to the weakness in the diagnostic criteria, which is a topic also covered here recently.

Perhaps there is hope in the brain systems / imaging-based approaches that are taking off as genome technology spreads into cognitive and imaging science. Tough to scan 10’s of thousands of people however. Double F**K!

I guess DSM-based psychiatric genetics is just about dead for the time being. The announcement of the soon to shutter deCODE Genetics and its 5-year stock price captures the failure of this endeavor.

Amidst a steady flow of upbeat research news in the behavioral-genetics literature, there are many inconvenient, uncomfortable, party-pooping sentiments that are more often left unspoken. I mean, its a big jump – from gene to behavior – and just too easy to spoil the mood by reminding your colleagues that, “well, everything is connected to everything” or “that gene association holds only for that particular task“. Such may have been the case often times in the past decade when the so-called imaging-genetics literature emerged to parse out a role for genetic variation in the structure and functional activation of the brain using various neuroimaging methods. Sure, the 5HTT-LPR was associated with amygdala activation during a face matching task, but what about other tasks (and imaging modalities) and other brain regions that express this gene. How could anyone (let alone NIMH) make sense out of all of those – not to mention the hundreds of other candidate genes poised for imaging-genetic research?

With this in mind, it is a pleasure to meet the spoiler-of-spoilers! Here is a research article that examines a few candidate genetic polymorphisms and compares their findings across multiple imaging modalities. In his article, “Neural Connectivity as an Intermediate Phenotype: Brain Networks Under Genetic Control” [doi: 10.1002/hbm.20639] Andreas Meyer-Lindenberg examines the DARPP32, 5HTT and MAOA genes and asks whether their associations with aspects of brain structure/function are in any way consistent across different neuroimaging modalities. Amazingly, the answer seems to be, yes.

For example, he finds that the DARPP32 associations are consistently associated with the striatum and prefrontal-striatal connectivity – even as the data were collected using voxel-based morphometry, fMRI in separate tasks, and an analysis of functional connectivity. Similarly, both the 5HTT and MAOA gene promoter repeats also showed consistent findings within a medial prefrontal and amygdala circuit across these various modalities.

This type of finding – if it holds up to the spoilers & party poopers – could radically simplify the understanding of how genes influence cognitive function and behavior. As suggested by Meyer-Lindenberg, “features of connectivity often better account for behavioral effects of genetic variation than regional parameters of activation or structure.” He suggests that dynamic causal modeling of resting state brain function may be a powerful approach to understand the role of a gene in a rather global, brain-wide sort of way. I hope so and will be following this cross-cutting “connectivity” approach in much more detail!

One way to organize the great and growing body of research into autism is via a sort-of ‘top-down’ vs. ‘bottom-up’ perspective. From the ‘top-down’ one can read observational research that carefully catalogs the many & varied social and cognitive attributes that are associated with autism. Often times, these behavioral studies are coupled with neurochemical or neuroimaging studies that test whether variation in such biomarkers is correlated with aspects of autism. In this manner, the research aims to dig down into the physiology and biochemistry of the developing brain to find out what is different and what differences might predict the onset of autistic traits. At the deepest biological level – the bedrock, so to speak – are a number of genetic variations that have been correlated with autism. These genetic variants permit another research strategy – a ‘bottom-up’ strategy that allows investigators to ask, “what goes wrong when we manipulate this genetic variant?” While proponents of each strategy are painfully aware of the limitations of their own strategy – oft on the barbed-end of commentary from the other side – it is especially exciting when the ‘top-down’ and ‘bottom-up’ methods find themselves meeting in the agreement in the middle.

So is the case with Nakatani et al., “Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism” [doi: 10.1016/j.cell.2009.04.024] who created a mouse that carries a 6.3 megabase duplication of a region in the mouse that luckily happens to be remarkably conserved in terms of gene identity and order with the 15q11-13 region in humans – a region that, when duplicated, is found in about 5% of cases with autism. [click here for maps of mouse human synteny/homology on human chr15] Thus the team was able to engineer mice with the duplication and ask, “what goes wrong?” and “does it resemble autism in any kind of meaningful way (afterall these are mice we’re dealing with)?”

Well, the results are rather astounding to me. Most amazing is the expression of a small nucleoar RNA (snoRNA) – SNORD115 (mouse-HBII52) – that function in the nucleolus of the cell, and plays a role in the alternative splicing of exon Vb of the 5HT2C receptor. The team then found that the editing of 5HTR2C was altered in the duplication mice and also that Ca++ signalling was increased when the 5HTR2C receptors were stimulated in the duplication mice (compared to controls). Thus, a role for altered serotonin function – which has been a longstanding finding in the ‘topdown’ approach – was met midway and affirmed by this ‘bottom-up’ approach! Also included in the paper are descriptions of the abberant social behaviors of the mice via a 3-chambered social interaction test where duplication mice were rather indifferent to a stranger mouse (wild-type mice often will hang out with each other).

Amazing stuff!

Another twist to the story is the way in which the 15q11-13 region displays a phenomenon known as genomic-imprinting, whereby only the mother or the father’s portion of the chromosome is expressed. For example, the authors show that the mouse duplication is ‘maternally imprinted’ meaning that that pups do not express the copy of the duplication that comes from the mother (its expression is shut down via epigenetic mechanisms that involve – wait for it – snoRNAs!) so the effects that they report are only from mice who obtained the duplication from their fathers. So, if you by chance were wondering why its so tough to sort out the genetic basis of autism – here’s one reason why. On top of this, the 5HTR2C gene is located on the X-chromosome which complicates the story even more in terms of sorting out the inheritance of the disorder.

Further weird & wild is the fact that the UBE3A gene (paternally imprinted) and the genetic cause of Angelman Syndrome sits in this region – as does the SNRPN gene (maternally imprinted) which encodes a protein that influences alternative RNA splicing and also gives rise to Prader-Willi syndrome. Thus, this tiny region of the genome, which carries so-called “small” RNAs can influence a multitude of developmental disabilities. Certainly, a region of the genome that merits further study!!